PI-11: EXTREME VARIABILITY OF THE PROGNOSTIC VALUE OF BIOLOGICAL PARAMETERS ACCORDING TO STATISTICAL METHODOLOGY IN PEDIATRIC SICKLE CELL DISEASE COHORT STUDIES
Authors: SOMMET J., LE ROUX E., KOEHL B., HAOUARI Z., BARUCHEL A., BROUSSE V., BENKERROU M., ALBERTI C.
Journal: HemaSphere (2022)

Purpose: Many paediatric studies describe the association between selected biological parameters and increased incidence of sickle cell disease (SCD) complications. However, blood levels of these biological parameters change over time (Figure 1), during growth and as the switch from foetal haemoglobin (Hb) to adult HbS is completed. In addition, blood levels may vary depending on the occurrence of complications, or during treatment. The aim of our study was to assess the impact of i) the methods used for biological parameters collection and use in cohort studies in the literature, ii) the statistical method used in subsequent analysis iii) the overall effect on the association between those biological parameters and clinical SCD outcomes in the paediatric context. Materials and methods: First, a literature search was performed to review how the biological parameters were collected and used in statistical analyses in published cohort studies in SCD. The second step was to test those statistical analyses on our cohort dataset of SCD patients in order to evaluate the impact of the methodological strategy on the results for this given cohort. In particular, we investigated the impact of statistical strategies on the relationship between biological parameters and macro-cerebral vasculopathy (CV) in our paediatric cohort of SCD patients followed at the Robert-Debré University Hospital. Results: In 16 cohort studies, biological parameters were collected either once or at different time-points during follow-up. The identified methods in the statistical analysis were: (1) one baseline value per patient (2) last known value; (3) mean of all values; (4) modelling of all values in a two-stage approach, which take into account the course of laboratory parameters over time. Applying these four different statistical methods to our cohort, the results and interpretation of the association between biological parameters and CV showed marked difference depending on the method used (Figure 1). Overall, the final number of significant parameters can differ from 1 to 4, depending on the statistical method. Furthermore, one biological parameter can be found significant with a method and not with another (Figure 2). In fact, using the Cox model encompassing linear multivariable modeling of longitudinal quantitative variables, on both clinical and biological parameters in our cohort, we identified some new independent protective or risk factors for CV. Years per upper-airway obstruction or bronchial obstruction and reticulocyte count were risk factors whereas foetal Hb level was protective. Specific treatment for upper or lower-airway obstruction and indirect targeting of foetal haemoglobin and reticulocyte count by hydroxycarbamide could potentially reduce the risk of CV. Conclusion: This study shows that different methods on the same dataset can lead to different conclusions as to the prognostic value of the laboratory parameters predicting the morbidity of SCD. It illustrates how important it is to apply appropriate statistical methods. In order to take into account longitudinal changes of biological parameters, appropriate statistical analyses in cohort studies should be considered.Figure 1. Evolution of fetal haemoglobin level and reticulocyte count over time. Biological parameters were recorded at least 3 weeks distant from any clinical event or any intensification (hydroxycarbamide, transfusion program, or haematopoietic stem celFigure 2. Illustration of results obtained according to the four methods used to study the relationship between the biological parameters and the occurrence of cerebral vasculopathy. Each panel represents one of the four methods used in multivariable anal The authors do not declare any conflict of interest